Identification of the molecular mechanism of nuclear receptor CAR-mediated liver carcinogenesis and its species differences.

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16352
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: University of Shizuoka
• Principal Investigator: Shizu Ryota 静岡県立大学, 薬学部, 助教 (50803912)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 核内受容体 / CAR / 化学発がん / 種差 / 肝細胞増殖

Outline of Final Research Achievements

Hepatic nuclear receptor CAR promotes hepatocyte proliferation and hepatocarcinogenesis in rodents. In this study, we have investigated the molecular mechanism of CAR-dependent hepatocyte proliferation and its species difference between human and rodents. Recently, we found nuclear accumulation of YAP was important for the CAR-dependent hepatocyte proliferation. Pull-down assay suggested that mouse CAR interacted with YAP but human CAR did not. With this assay, we found the WW domain in YAP as an interaction interface. WW domains are reported to interact with a specific amino acid sequence PPXY (PY motif) and mouse CAR contain the motif (PPAY) but human CAR has the mutated motif (PPAH). In this study, we found that mouse CAR interacted with YAP via the PY motif-WW domain interaction and activated YAP to induce hepatocyte proliferation. The absence of the PY motif in human CAR may result in the lack of interaction with YAP and thus CAR-dependent hepatocyte proliferation.

Free Research Field

化学発がん

Academic Significance and Societal Importance of the Research Achievements

化学物質の齧歯動物を用いた発がん性試験において、核内受容体CARの活性化に伴う肝発がんが認められる。これはヒトでは起こらないとされているが、その分子機序が明確ではないため、CARの活性化が実際にヒトにおいて肝がんを引き起こすか否かは明らかではない。化学物質による発がん性は、医薬品や農薬等、新規化学物質の開発中止の原因になりうる重要な情報であるにも関わらず、このようなヒト外挿性の曖昧さは安全性の観点から問題である。齧歯動物におけるCAR依存的肝発がんの分子機序、種差の原因を明らかにした本研究成果は、化学物質の安全性を考慮する上で非常に有益な情報となる。